The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56-81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17-25%, based on total polymer concentration, when compared with pure diclofenac sodium.